Measuring waning protection from seasonal influenza vaccination during nine influenza seasons, Ontario, Canada, 2010/11 to 2018/19

Background Waning immunity from seasonal influenza vaccination can cause suboptimal protection during peak influenza activity. However, vaccine effectiveness studies assessing waning immunity using vaccinated and unvaccinated individuals are subject to biases. Aim We examined the association between time since vaccination and laboratory-confirmed influenza to assess the change in influenza vaccine protection over time. Methods Using linked laboratory and health administrative databases in Ontario, Canada, we identified community-dwelling individuals aged ≥ 6 months who received an influenza vaccine before being tested for influenza by RT-PCR during the 2010/11 to 2018/19 influenza seasons. We estimated the adjusted odds ratio (aOR) for laboratory-confirmed influenza by time since vaccination (categorised into intervals) and for every 28 days. Results There were 53,065 individuals who were vaccinated before testing for influenza, with 10,264 (19%) influenza-positive cases. The odds of influenza increased from 1.05 (95% CI: 0.91–1.22) at 42–69 days after vaccination and peaked at 1.27 (95% CI: 1.04–1.55) at 126–153 days when compared with the reference interval (14–41 days). This corresponded to 1.09-times increased odds of influenza every 28 days (aOR = 1.09; 95% CI: 1.04–1.15). Individuals aged 18–64 years showed the greatest decline in protection against influenza A(H1N1) (aORper 28 days = 1.26; 95% CI: 0.97–1.64), whereas for individuals aged ≥ 65 years, it was against influenza A(H3N2) (aORper 28 days = 1.20; 95% CI: 1.08–1.33). We did not observe evidence of waning vaccine protection for individuals aged < 18 years. Conclusions Influenza vaccine protection wanes during an influenza season. Understanding the optimal timing of vaccination could ensure robust protection during seasonal influenza activity.

a Influenza seasons with known vaccine mismatch (and consequently low influenza vaccine effectiveness) in Canada.
b The start of the influenza season was determined to be the beginning of the week (Sunday) when the proportion of individuals testing positive for influenza exceeded 5%.The end of the season was Saturday prior to the week when the proportion of influenza-positive individuals fell below 5%.c Information on the strains in the influenza vaccines available in Ontario is from the product monographs of the vaccines from each respective influenza season.d Proportions were calculated based on the end-of-season total number of positive influenza specimens by type and subtype in Ontario according to the weekly influenza reports from the Public Health Agency of Canada.Unsubtyped influenza A cases were assumed to have the same distribution as subtyped influenza A cases and were re-classified accordingly.Similarly, influenza B cases were assumed to have the same lineage distribution as influenza B cases in Canada that were antigenetically characterized by the National Microbiology Laboratory and were re-classified accordingly.
e Approximately 49% of all influenza A specimens in Ontario's health administrative databases were subtyped.Unsubtyped influenza A cases were assumed to have the same distribution as subtyped influenza A cases and were re-classified accordingly.Lineage information was not available for majority of influenza B cases.

Results of model-building exercises.
A. Identifying confounders in the association between time-since-vaccination groups and laboratory-confirmed influenza:

Supplementary Table S2. Characteristics of community-dwelling individuals aged ≥6 months vaccinated against seasonal influenza before influenza testing by time since vaccination during the 2010-2011 to 2018-2019 influenza seasons in Ontario, Canada. Time since vaccination to specimen collection date Characteristic 14-41 days 42-69 days 70-97 days 98-125 days 126-153 days ≥154 days N=6,774 N=11,987 N=13,947 N=11,255 N=7,782 N=1,320
*Variables bolded were statistically significant (p<0.05) in univariate associations with the exposure (time-since-vaccination group) and outcome (laboratory-confirmed influenza) and were included in the main model as confounders.B.Assessing the percent change in the beta-coefficients for time-since-vaccination groups when adjusting for each confounder in a logistic regression model: a The proportions by influenza type/subtype (including those missing information) were calculated among individuals positive for influenza for each time-since-vaccination group.bTheproportionswith 'any children complex chronic condition' was calculated among individuals aged 6-59 months only (n=1,082).Supplementary TableS3.

Characteristics of community-dwelling individuals aged ≥6 months vaccinated against seasonal influenza before influenza testing during the 2010-2011 to 2018-2019 influenza seasons in Ontario, Canada, by influenza status and by type/subtype a .
a Among the vaccinated cases, 5,901 (57%) had type/subtype information.bTheproportionswith 'any children complex chronic condition' was calculated among individuals aged 6-59 months only (n=1,082).cRangesarepresented to avoid back calculation of counts ≤5.Supplementary TableS4.

Odds ratios (OR) by time since vaccination (TSV) against any laboratory-confirmed influenza infection in community- dwelling individuals aged ≥6 months in Ontario, Canada during the 2010-2011 to 2018-2019 season, by age groups.
Counts with ≤5 vaccinated cases were suppressed and estimates were replaced with NE (not estimable).Estimates where the reference group (i.e., 14-41 days) had ≤5 vaccinated cases were replaced with NE.Ranges are presented to avoid back calculation of counts ≤5.b Cochran-Armitage trend tests were conducted to determine the association between time since vaccination group (a categorical variable modelled as a continuous variable) and laboratory-confirmed influenza.P-values for trend tests were marked on the estimate for the last interval (≥154 days); *p <0.05; ** p≥0.05.A P-value <0.05 implies a trend between time since vaccination categories and laboratory-confirmed influenza.c Time since vaccination per 28 days were modelled using restricted cubic splines and its regression coefficients were used to test for linearity.P-values for linearity tests were marked on the calculated estimate; †p <0.05; † †p≥0.05.A P-value ≥0.05 implies that time since vaccination per 28 days is linearly associated with the logit of the outcome (i.e., accepting the null hypothesis that the restricted cubic spline coefficients are zero). a

Table S6 . Odds ratios (OR) by time since vaccination (TSV) against laboratory-confirmed influenza infection of the predominant circulating strain(s) in community-dwelling individuals aged ≥6 months in Ontario, Canada by influenza season. Restricted to vaccinated individuals tested between October 1 st and March 31 st of the following year Restricted to vaccinated individuals tested during influenza activity
October 1 st , 2013 -March 31 st , 2014 December 1 st , 2013 -May 24 th , 2014